Abstract: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants and children and is also a predictable cause of respiratory illness in persons of all ages. During RSV infection, a key target of host immune response is the fusion (F) protein. Although the neutralizing epitopes of F have been identified within the three-dimensional model of the RSV F homotrimer, our understanding of the structure-immunogenicity relationship between RSV F epitopes and the humoral immune response remains incomplete. Significant questions remain such as: 1) immunodominance, if any, of the RSV F epitopes;2) the effect of pre/post fusion conformational state transition on the stability and solvent exposure of antigenic sites; 3) the relative importance of tertiary domain structures and F oligomerization for neutralizing antibody generation, potency, and recognition;and 4) the avidity and affinity of neutralizing and non-neutralizing antibodies to RSV F epitopes. To address these fundamental questions, we have formed an interdisciplinary academic partnership and have established three Specific Aims, each designed to address a key component of the proposed project. We will first rationally design, synthesize, and purify RSV F subdomains bearing &#8805;1 neutralizing epitopes. We will then use such proteins in two lines of complementary experiments: 1) characterization of the quality and quantity of antigenic site-specific neutralizing antibody response to specific RSV F epitopes during primary and secondary RSV infection in rodents and humans;and 2) immunogenicy and protective efficacy of structurally distinct RSV F subdomains, especially when presented in the context of human papillomavirus (HPV) L1 capsid scaffolds such as pentamers (capsomeres) and virus-like particles (VLPs);recent evidence suggests that each of these vaccine platforms can function as a self-adjuvanting antigen delivery system that elicits broad cellular and humoral immune responses against heterologous antigens. Our approach utilizes the collection of unique reagents and expertise as well as scientific innovations in molecular biology, virology, immunology, vaccine development, and structural biology among the research institutions and personnel. The proposed experiments are expected to further our understanding of host humoral immune response during RSV infection, with implications for RSV diagnostics, clinical study design, and vaccine development.